This invention relates to dialysis and hemodiafiltration in general and, more particularly, to improved hemodiafiltration methods and devices for removal of blood toxins.
Hemodialysis and Hemodiafiltration are well known methods for removing toxic substances from a patient""s blood, thereby reducing the level of toxins in the patient""s blood as part of an extracorporeal blood cleansing system. Both these methods are based on flowing blood through a cartridge containing a semi-permeable membrane which separates the cartridge into two compartments. In general, hemodialysis is a process whereby blood flows through a blood-side compartment of the cartridge, while a cleansing solution, i.e., a dialysate solution, flows through a dialysate-side compartment of the cartridge. Toxins are removed from the blood by diffusion across the semi-permeable membrane from the blood-side compartment to the dialysate-side compartment. The rate of diffusion is determined by the concentration gradient established between a higher concentration of toxins in the blood relative to the dialysate fluid. Hemodiafiltration is process whereby the normal removal of toxins by diffusion is augmented by a convective flow of plasma water across the semi-permeable membrane which assists in carrying toxins by bulk flow of fluid from the bloodside of the membrane to the dialysate side of the membrane. The transportation of plasma water across the semi-permeable membrane is achieved by establishing a pressure gradient, generally referred to as Transmembrane Pressure (TMP), across the membrane. In hemodiafiltration, an equivalent amount of a substitution fluid, or replacement fluid, must be added to the blood to replace the plasma water that is filtered across the membrane. This substitution fluid is generally added either before the blood enters the cartridge (pre-dilution mode) or after the blood exits the cartridge (post-dilution mode).
Hemodiafiltration systems using two cartridges connected in series are also known in the art. In such systems, a first cartridge is used as a conventional diafiltration cartridge providing simultaneous diffusion and filtration of plasma water across the semi-permeable membrane. In a second cartridge, toxins are diffused from the blood to the dialysate fluid, and a reverse pressure gradient is used to reverse-filter dialysate fluid from the dialysate-side compartment, across the membrane, and into the blood-side compartment. The reverse-filtered dialysate fluid serves as a substitution fluid to replace the amount of plasma water that is filtered from the blood-side compartment to the dialysate-side compartment in the first cartridge. Such a method is described in J. H. Miller et al., xe2x80x9cTechnical Aspects of High-Flux Hemodiafiltration for Adequate Short (Under 2 Hours) Treatment,xe2x80x9d Transactions of American Society of Artificial Internal Organs (1984), pp. 377-380.
Certain hemodialysis/diafiltration applications use two cartridges connected in series. The dialysate fluid in the first cartridge is made hypertonic or hypotonic (by adjusting the electrolyte levels of the dialysate stream) to improve toxin removal efficiency. This method is disclosed in PCT Application No. PCT/US99/25804 entitled xe2x80x9cNon-Isosmotic Diafiltration Systemxe2x80x9d filed in the name of Collins et al., the entirety of which is hereby incorporated by reference.
One embodiment of the present invention includes a method whereby hydrogen ion concentration (or pH) of the dialysate fluid entering a first filtration cartridge is reduced by introducing a secondary acid solution. The second filtration cartridge then serves to correct for blood pH shifts occurring in the first filtration cartridge. One advantage of this method is that it allows one to carry out the diffusion and/or diafiltration process in the first cartridge outside the normal limit of blood pH. This method improves the removal of certain substances, such as protein-bound substances that disassociate more readily from proteins at low pH. This method also allows for enhanced removal of other substances that may be affected by changes in the number of charged polar groups (acidic or basic) and/or structural changes of blood proteins (i.e., those proteins circulating in the blood stream or those protein that accumulate and/or adsorb near the semi-permeable membrane) due to changes in pH.
An additional benefit is possible when the acid that is used in the dialysate stream of the first cartridge is citric acid. In this case, the ionized citrate molecule can diffuse into the blood compartment of the first cartridge where it binds to ionized calcium. This has the potential effect of reducing the amount of clotting in the cartridges as citrate has certain anti-coagulation properties. Ionized calcium is replaced in the blood stream by back diffusion and/or back filtration of calcium from the standard dialysate that passes through the second cartridge. If substitution fluid is introduced between the two cartridges as described above, this also acts as a source of calcium for the blood stream.
It is a further object of the invention to provide hemodialysis or hemodiafiltration method using two cartridges (or two stages), preferably in series, that improves clearance of certain substances by introducing an acidic solution into the dialysate fluid stream of the first cartridge. The process is such that blood in the first cartridge is dialyzed or diafiltered against a low pH dialysate solution, while blood in the second cartridge is dialyzed or diafiltered against a standard dialysate (i.e., within a pH range from 7.0 to 7.8). The second cartridge then may serve three main functions which are 1) to correct for blood pH shifts caused by the low pH dialysate in the first cartridge, 2) to continue to remove blood toxins by diffusion or diafiltration against standard dialysate, and 3) to correct for electrolyte imbalances in the blood. In a hemodialysis application, correction of blood pH and electrolyte imbalance is accomplished by diffusion of neutralizing substances (such as bicarbonate) and electrolytes across the semi-permeable membrane separating the blood and dialysate compartments of the second cartridge. In a hemodiafiltration application, these corrections are accomplished by introducing a substitution fluid containing neutralizing substances (such as bicarbonate) and electrolytes into the blood stream in addition to diffusion across the semi-permeable membrane of the second cartridge.
The present invention may be embodied in an improved dialysis machine that allows for the addition of a secondary acid solution into the dialysate fluid path. The machine may include other basic components used in current dialysis machines, such as a water preparation module to degas and heat water necessary for preparing dialysate, an ultrafiltration control system which may include a flow balancing system and an ultrafiltration (UF) pump, a dialysate proportioning system which may introduce dialysate concentrates into the water stream, and extracorporeal monitoring and control components which may include a blood pump for circulating blood through the extracorporeal circuit.
When performing hemodiafiltration, a system of the present invention may include a substitution fluid system (including pump and substitution fluid filters when preparing a substitution fluid on-line using dialysate fluid), and an interdialysate flow control system (which may include an interdialysate pump) to regulate the relative ultrafiltration rates of the two dialyzer cartridges.
In a preferred embodiment, blood to be cleansed flows into a first dialyzer or diafilter cartridge. The cartridge contains a semi-permeable membrane that separates the cartridge into two compartments, a first compartment containing the blood to be cleansed, and a second compartment containing a dialysate fluid. The pH of the dialysate fluid in this compartment is reduced below that of standard dialysate (i.e., pH less than 7.0) by addition of a second acid stream (such as citric acid) before the dialysate is delivered to this first dialyzer cartridge. The effect of this is to decrease the pH of the blood in order to enhance removal of certain substances. These substances might include protein-bound substances that may dissociate at lower pH conditions or other substances that may be affected by changes in the number of charged polar groups (acidic or basic) of proteins in the blood stream. For the special case of using citric acid, the effect may also include a decrease in blood clotting in the extracorporeal circuit due to the anti-coagulation properties of citrate.
As blood flows through the blood compartment of the first dialyzer cartridge, in addition to the pH of the blood being lowered, toxins are removed by diffusion resulting from a concentration gradient between the blood and the dialysate fluid. Also, electrolytes may be imbalanced depending on the amount of dilution that may or may not occur as a result of adding the acid stream to the dialysate fluid. If performing diafiltration, an additional removal of toxins may occur by convection as a portion of plasma water from the blood compartment is filtered across the semi-permeable membrane and into the dialysate compartment.
Upon exiting the first dialyzer cartridge, the partially dialyzed/diafiltered blood may be mixed with a substitution fluid. The substitution fluid helps correct the pH shift and electrolyte imbalance resulting from the first cartridge process since the substitution fluid contains necessary neutralizing agents, such as a bicarbonate, and proper electrolyte levels.
The blood then enters a second dialyzer cartridge. In this second cartridge, the blood is dialyzed (or diafiltered) against a standard dialysate containing electrolytes within their normal ranges. Blood toxins continue to move across the semi-permeable membrane into the dialysate fluid by diffusion (and perhaps by convection), while electrolytes and neutralizing agents from the dialysate may move across the semi-permeable membrane and into the blood. Upon existing the second cartridge, the blood pH and composition of electrolytes are within normal ranges.
Dialysate fluid is prepared by proportioning dialysate concentrates with a treated water as is known in the art. Flow of the dialysates fluid into and out of the dialyzer cartridges is controlled precisely using a flow balance system that is known in the art. In treating a patient according to the present invention, the device typically must remove a portion of plasma water in order to maintain the patient""s dry weight. This can be done using an ultrafiltration pump as is known in the art. When performing diafiltration, substitution fluid may be generated on line using a portion of the fresh dialysate fluid by filtering it through at least one sterilizing filter or substitution fluid filter.
Fresh dialysate enters into the dialysate inlet of the second cartridge, where it may flow countercurrent to the blood flow. As the dialysate fluid traverses the cartridge, toxins and ultrafiltered plasma water from the blood begin to accumulate in the dialysate fluid. Some electrolytes and neutralizing agents from the dialysate may be depleted from the dialysate fluid as they move from the higher concentration in the dialysate to the lower concentration in the blood.
The partially spent dialysate fluid exiting the dialysate outlet of the second cartridge is mixed in a mixing chamber with a metered portion of an acid solution (preferably a citric acid solution) to reduce the dialysate pH to below 7.0. In one embodiment, the acid solution source is a saturated solution obtained by flowing a portion of treated water through a closed container containing the powdered form of dry acid. In a second embodiment, the acid solution is introduced from an externally supplied container using a pump. The mixed dialysate stream then flows toward the dialysate inlet of the first cartridge. A regulator which controls the relative amounts of plasma water filtered off in the two cartridges may be used. For example, a servo- controlled interdialysate pump that changes speed based on an algorithm calculated using measured pressure differentials (TMP""s) across the semi-permeable membrane may be used.
The partially spent acidic dialysate fluid then enters the dialysate inlet of the first cartridge. As it flows through the cartridge, blood toxins and filtered plasma water may accumulate in this fluid. The low pH of this dialysate fluid results in an imbalance of hydrogen ions across the membrane such that the pH of the blood may decrease below its normal range. In the preferred example using citric acid, additional anticoagulation properties may be gained due to the inherent properties of citrate as an anticoagulant. The spent dialysate fluid exits the first cartridge and flows back toward the flow balance system where it eventually flows out to the drain.
It should be apparent to those skilled in the art that this method can be performed with at least two dialyzer cartridges operation in a typical dialysis mode or it can be performed with two high flux dialyzer or diafiltration cartridges is a hemodiafiltration mode. The limiting factor being the ability of the second cartridge to recover from the perturbation caused by the first cartridge. A preferred method includes the diafiltration mode whereby the substitution fluid is introduced into the blood stream between the two cartridges, so as to help restore the blood back to its normal ranges prior to infusion to a patient.